The focus of rationally targeted therapies is to identify molecular-genetic alterations specific to tumor cells that are necessary for maintenance of the malignant phenotype. The viral oncoproteins of human papillomavirus (HPV), E6 and E7, are such targets for HPV-associated malignancies. The viral oncoproteins E6 and E7 are consistently expressed in HPV-associated cancers, are necessary for maintenance of the malignant phenotype, and have no known homology to human proteins. E6 and E7 oncoproteins are therefore ideal targets for immunomodulatory therapies designed to augment the cellular immune response to a tumor-specific antigen. Our group has developed a therapeutic, naked DMA vaccine (pNGVL4a-HPV16 Sig/E7(detox)/HSP70) designed to enhance the cellular immune response to the E7 protein expressed by HPV16-positive tumors. This vaccine has demonstrated significant potency in preclinical model systems against established E7-expressing murine tumors and minimal toxicity in preclinical toxicology studies. Recently, HPV16 has been determined to play an etiologic role for a distinct subset of head and neck squamous cell carcinomas (HNSCC), thus providing a new therapeutic target for this malignancy. We hypothesize that administration of pNGVL4a-HPV16 Sig/E7(detox)/HSP70 vaccine to patients with a diagnosis of HPV16-positive HNSCC will augment the cellular immune response to E7 protein, eradicate minimal residual disease, and improve disease-specific survival in future phase III trials. The overall objective of this proposal is to evaluate the feasibility, safety and immunogenicity of pNGVL4a-HPV16 Sig/E7(detox)/HSP70 by performing a phase I open-label dose escalation trial of four intramuscular vaccinations administered in the adjuvant setting to patients with Stage III and IV HPV16-positive HNSCC cancer. Clinical grade pNGVL4a-HPV16 Sig/E7(detox)/HSP70 has been produced with support from the Rapid Access to Intervention Development (RAID) program and The Investigational New Drug Application (BB-IND 11713) has been approved by the Food and Drug Administration. This application is written to request financial support for the clinical trial, including research nurse support, data management support, clinical trails compliance and auditing services, and clinical specimen processing and storage. [unreadable] [unreadable] [unreadable]